he purpose of this application is to elucidate the interaction of HIV infection and alcohol use disorders on central nervous system morbidity and the additional complications of aging arising from extended longevity afforded by advances in anti-HIV pharmacotherapies. Adding to this aging HIV-infected cohort are the increasing numbers of people over 50 years old who are being newly infected. Even in relatively healthy individuals, the aging brain is increasingly vulnerable to endogenous and exogenous insult, an example being the age-alcoholism interaction on brain tissue volume and integrity. Similarly, age-related decline in neural system integrity can compound the HIV-vulnerable brain systems and increase liability for dementia. Further compounding the picture of HIV infection is the common comorbidity of hepatitis C infection (HVC) and the sequelae of AIDS-defining events. Thus, investigation of interactions of normal aging, alcohol use disorders, and HIV infection is now especially germane given the aging HIV-infected population. The proposal builds on our research to date that includes individuals in four groups [HIV + Alcoholism (HIV+ALC), HIV without Alcoholism (HIV), Alcoholics (ALC), Normal Control Subjects (NCS)], examined upwards of 5 times over 8 years with multimodal neuroimaging [structural MRI and diffusion tensor imaging (DTI)], clinical and behavioral assessment, and neuropsychological testing. Results of our analyses demonstrate that the aging brain is highly sensitive to the combined effects of HIV/AIDS, alcoholism, and HCV infection. We now propose to follow our existing longitudinal cohort of over 100 participants (more than half of whom are now over 50 years old) and to recruit an additional 100 individuals age 50 or older who will be followed at 18-month intervals with neuroimaging [MRI, DTI, resting state MRI (rsMRI), and cerebral perfusion measured with pulsed-continuous arterial spin labeling (PCASL)], clinical, neuropsychological, and clinical assessment, including determination of circulating proinflammatory cytokine levels. Aim 1: Establish the pattern of brain pathology with MR imaging and functional measures in an expanded sample of older individuals with HIV infection and the combined morbidity of alcohol abuse. Cross-sectional hypotheses predict a complex pattern of additive and interactive effects. Aim 2: Assess longitudinal disease trajectory (progression or effective control) as modulated by alcohol abuse, HCV infection, and ART compliance by testing the current and new cohorts at 18-month intervals. Aim 3: Establish cross-sectional and longitudinal within-subject relationships among neuroimaging measures, cognitive and motor performance, and clinical status. ! PUBLIC HEALTH RELEVANCE: Aging, alcoholism, HIV/AIDS, and the common comorbidity of hepatitis C infection each has deleterious effects on brain structure, function, and quality of lif. With improved medication HIV infected individuals are living into older age, and there is an increase in the number of people who become newly infected with HIV after they are over 50 years old. The proposed study will use longitudinal neuroimaging to identify brain insults underlying the interaction of HIV infection and alcohol abuse with aging and explore how they contribute to the deterioration in clinical, cognitive, and motor abilities in the context of the ultimate frailty of old age.